Impaired retinol utilization inAdh4 alcohol dehydrogenase mutant mice
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Adh4, a member of the mouse alcohol dehydrogenase (ADH) gene family, encodes an enzyme that functions in vitro as a retinol dehydrogenase in the conversion of retinol to retinoic acid, an important developmental signaling molecule. To explore the role of Adh4 in retinoid signaling in vivo, gene targeting was used to create a null mutation at the Adh4 locus. Homozygous Adh4 mutant mice were viable and fertile and demonstrated no obvious defects when maintained on a standard mouse diet. However, when subjected to vitamin A deficiency during gestation, Adh4 mutant mice demonstrated a higher number of stillbirths than did wild-type mice. The proportion of liveborn second generation vitamin A-deficient newborn mice was only 15% for Adh4 mutant mice but 49% for wild-type mice. After retinol administration to vitamin A-deficient dams in order to rescue embryonic development, Adh4 mutant mice demonstrated a higher resorption rate at stage E12.5 (69%), compared with wild-type mice (30%). The relative ability of Adh4 mutant and wild-type mice to metabolize retinol to retinoic acid was measured after administration of a 100-mg/kg dose of retinol. Whereas kidney retinoic acid levels were below the level of detection in all vehicle-treated mice (<1 pmol/g), retinol treatment resulted in very high kidney retinoic acid levels in wild-type mice (273 pmol/g) but 8-fold lower levels in Adh4 mutant mice (32 pmol/g), indicating a defect in metabolism of retinol to retinoic acid. These findings demonstrate that another retinol dehydrogenase can compensate for a lack of Adh4 when vitamin A is sufficient, but that Adh4 helps optimize retinol utilization under conditions of both retinol deficiency and excess. Dev. Genet. 25:1–10, 1999. © 1999 Wiley-Liss, Inc.Keywords:
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Retinoic acid has recently been shown to increase growth hormone (GH)-gene transcription rate and GH synthesis in vitro. To investigate the role retinoic acid plays in the neuroregulation of GH secretion we have studied GH responses to growth hormone-releasing hormone (GHRH) in retinoic acid-deficient rats. Compared to normally fed male rats, retinoic acid-deficient rats showed a marked impairment in body weight, which was statistically significant after 3 weeks and maximal after 5-6 weeks (p < 0.001). Yet, in vivo GH responses to different doses of GHRH (1, 5 and 25 µg/kg) in pentobarbital-anesthetized rats were similar in both groups. Also, in vitro GH responses to GHRH, forskolin, and KC1 were similar in perfused pituitary cells taken from control and retinoic acid-deficient rats. However, further studies carried out in freely-moving rats showed the typical GH secretory pattern usually found in male rats of the control group, while retinoic acid-deficient rats displayed a highly variable GH secretory pattern with GH peaks of much lower amplitude. Finally, after gel electrophoresis of in vitro 35S-labelled proteins, no differences were observed in the molecular forms of GH. Considering these findings on normal pituitary responsiveness and alterations in GH pulsatility, our data suggest that retinoic acid deficiency leads to an alteration in the neuroregulation of GH secretion at the central level.
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It has previously been shown in this laboratory that vitamin D3 is essential for normal insulin secretion from the perfused rat pancreas. In this present study, the influence of vitamin D status on insulin secretion in vivo was investigated. Intravenous glucose tolerance tests were performed on conscious vitamin D-deficient rats (-D), vitamin D-replete rats fed ad libitum (+D AL), and vitamin D-replete rats pair fed to the D-deficient animals (+D PF). Vitamin D deficiency, easily recognizable by low daily dietary intake and depressed plasma calcium levels, was found to impair plasma glucose clearance as characterized by an elevated KG value (representing a function of the area beneath the tolerance curve). KG values for the +D AL, +D PF, and -D groups were 504 +/- 15, 480 +/- 46, and 641 +/- 28, respectively. The increase in KG corresponded to a significant reduction in glucose-mediated insulin secretion as compared to the +D animals. This difference appeared not to be related to the increase caloric intake associated with vitamin D repletion, since +D rats which had been pair fed to the -D animals also exhibited restored plasma insulin levels in response to glucose. Plasma phosphorus concentrations were comparable in all three groups, and thus this parameter is also unlikely to be a contributory factor in the observed phenomenon. Additional experiments were conducted to evaluate the involvement of hypocalcemia in the observed impaired glucose tolerance. Normalization of plasma calcium levels (from 4.8 mg/100 ml to 9.6/100 ml) of the -D rats, by dietary calcium and phosphorus manipulation, failed to improve glucose clearance (KG for -D normocalcemic rats = 639 +/- 61) or insulin secretion. These results support the concept that vitamin D plays a physiological role in insulin secretion, acting, at least in part, independently of nutritional factors and the prevailing plasma calcium and phosphorus concentrations.
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Retinoic acid (vitamin A acid), the carboxylic acid corresponding to the primary alcohol retinol (vitamin A), has previously been thought to fulfil all the functions of vitamin A except in vision, since rats fed a diet deficient in retinol but supplemented with retinoic acid grow well, outwardly appearing healthy, yet become blind. This paper reports that female rats on such a diet had normal oestrous cycles and became pregnant when mated, but always resorbed the foetuses and no litters were born. The first abnormalities detected were necrosis and slight polymorph infiltration around the periphery of the placental disk about the sixteenth day of pregnancy. Supplementation with retinol as late as the tenth day resulted in the birth of a healthy litter. Retinoic acid therefore maintained the early but not the later stages of gestation. When very small amounts of retinol were given during pregnancy, dead or weak young were born; on higher supplements of the vitamin, litters were weaned successfully. By this means young rats were produced with negligible stores of retinol. Male rats fed retinoic acid but not retinol had small and often oedematous testes. The germinal epithelium sloughed off and in some tubules the lumen was obliterated, but in others the lumen remained, and in these some spermatocytes and spermatogonia were held tenaciously. The seminal vesicles were smaller than in controls given retinol. In rats born with negligible stores of retinol—see above—and maintained on retinoic acid, the testes remained infantile; spermatids were never formed. Feeding retinol restored spermatogenesis in degenerate testes and promoted the normal development of testes that had remained infantile; it also ensured the growth of the seminal vesicles. Retinoic acid did not therefore serve in reproduction, although it replaced the true vitamin in maintaining life, growth and general health. Besides the latter so-called systemic function, vitamin A must have a discrete and specific role in reproduction, viz. that performed by retinol but not by retinoic acid. From among the many previously reported features of disordered reproduction in vitamin A-deficient animals, it was possible to distinguish which had arisen from a failure of this specifically ‘reproductive’ role and which from a ‘systemic’ deficiency. The inactivity of retinoic acid in reproduction demonstrates that in rats vitamin A has not two, as previously thought, but three dissociable modes of action: (1) systemic; (2) in vision; and (3) in reproduction.
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The effect of feeding retinoic acid for 2 and 6 days on the metabolism of labeled retinol in tissues of rats maintained on a vitamin A deficient diet was studied. The metabolites of retinol were analyzed by high performance liquid chromatography. Feeding retinoic acid for 2 days significantly reduced the blood retinol and retinyl ester levels without affecting the vitamin A content of the liver. In intestine and testis the content of labeled retinoic acid was decreased significantly by dietary retinoic acid. Addition of retinoic acid to the diet for 6 days resulted, in addition to decreased blood retinol and retinyl ester values, in an increase in the retinyl ester values in the liver. The accumulation of retinyl ester in the retinoic acid fed rat liver was accompanied by an absence of labeled retinoic acid. Kidney tissue was found to contain the highest levels of labeled retinoic acid, retinol, and retinyl esters; dietary retinoic acid did not alter the concentrations of these retinoids in the kidney during the experimental period. Since kidney retained more vitamin A when the liver vitamin A was low and also dietary retinoic acid did not affect the concentrations of radioactive retinoic acid in the kidney, it is suggested that the kidney may play a major role in the production of retinoic acid from retinol in the body.Key words: retinol, retinoic acid, vitamin A deficiency, tissue metabolites, rat.
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To clarify the role of vitamin D in the regulation of the endocrine pancreas, we have studied insulin and somatostatin secretion in vitamin D deficient rats (reared on a vitamin D deficient diet), D-replete rats (reared on a vitamin D deficient diet and given 160 IU of vitamin D3 sc twice a week) and control rats (reared on laboratory chow), using the isolated perfused rat pancreas. In the vitamin D deficient rats, the perfusate insulin induced by 16.7 mM glucose was only 35% of the secretion in the control rats. In the D-replete rats, the insulin release was restored to that of the controls. Similarly, the plasma insulin level in the vitamin D deficient rats was very low and the level in the D-replete rats was also restored to the level of the controls. The perfusate somatostatin response to glucose was not significantly different in any of the three groups. In addition, since the plasma calcium level in the vitamin D deficient rats was very low and in the D-replete rats was still lower, compared to normal rats, we suggest that vitamin D acts not only via the plasma calcium level but possibly also directly on the B cell.
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